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1 M I N I S T R Y O F F O O D A N D D R U G S A F E T Y

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3 머리말

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5 목 차 CODEX 분석용어가이드라인 서론 3 분석용어정의 4 첨부 Ⅰ. 분석분야에사용되는용어비교 33 Ⅱ. GUIDELINES ON ANALYTICAL TERMINOLOGY (CAC/GL ) 39 색인 57

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7 CODEX 분석용어가이드라인

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9 서론 3

10 분석용어정의 Accuracy ( 정확도 ) Analyte ( 분석물질 ) Applicability ( 적용가능성 ) 4

11 Bias ( 편향성 / 바이어스 ) Calibration ( 교정 ) 5

12 Certified reference material, CRM ( 인증표준물질 ) Conventional quantity value ( 협정값 ) 6

13 Critical value, L C ( 임계값 ) α α α 7

14 Defining (empirical/conventional) method of analysis [ 분석법의 ( 경험적 / 관례적 ) 규정 ] Error ( 오차 ) Expanded measurement uncertainty ( 확장측정불확도 ) 8

15 Fitness for purpose ( 합목적성 ) HorRat ( 호렛값 ) 9

16 Inter-laboratory study ( 실험실간비교시험 ) Laboratory-performance (proficiency) study [ 검사능력 ( 숙련도 ) 평가 ] 10

17 Limit of detection, LOD ( 검출한계 ) β α β α σ α β σ 11

18 α β σ Limit of quantification, LOQ ( 정량한계 ) σ σ σ σ σ σ σ σ α β 12

19 Linearity ( 직선성 ) Material-certification Study ( 시료인증연구 ) Measurand ( 측정량 ) 13

20 Measurement method ( 측정방법 ) Measurement procedure ( 측정절차 ) 14

21 Measurement uncertainty ( 측정불확도 ) 15

22 Method-performance study ( 분석법성능시험 ) Metrological traceability ( 측정소급성 ) 16

23 Outlier ( 이상값 ) 17

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25 Precision ( 정밀도 ) Quality assurance ( 품질보증 ) 19

26 Rational method of analysis ( 합리적분석법 ) Recovery/recovery factors ( 회수 / 회수율 ) 20

27 Reference material ( 표준물질 ) Reference value ( 기준값 ) 21

28 Repeatability (reproducibility) [ 반복성 ( 재현성 )] Repeatability conditions ( 반복성조건 ) 22

29 Repeatability (reproducibility) limit [ 반복성 ( 재현성 ) 한계치 ] σ Repeatability (reproducibility) standard deviation ( 반복성 ( 재현성 ) 표준편차 ) 23

30 Repeatability (reproducibility) relative standard deviation (coefficient of variation) [ 반복성 ( 재현성 ) 상대표준편차 ( 변동계수 )] Reproducibility conditions ( 재현성조건 ) Result ( 결과 ) 24

31 Robustness (ruggedness) ( 완건성 ( 둔감도 )) 25

32 Selectivity ( 선택성 ) Sensitivity ( 민감도 ) Surrogate ( 대체물 ) 26

33 Systematic error ( 계통오차 ) Trueness ( 진도 ) True value ( 참값 ) 27

34 Validation ( 밸리데이션 / 유효화 ) Validated test method ( 밸리데이션된시험법 ) 28

35 Validated range ( 밸리데이션된범위 ) Verification ( 검증 ) 29

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37 첨부 Ⅰ. 분석분야에사용되는용어비교 Ⅱ. GUIDELINES ON ANALYTICAL TERMINOLOGY (CAC/GL )

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39 Ⅰ. 분석분야에사용되는용어비교 영문 위해분석용어 의약품등시험방법 해설집 밸리데이션에대한 가이드라인해설서 2) 과학기술용어집 3) 한국표준과학연구원 기술표준원 KS CODEX 측정학용어사전 4) 용어 5) 규정번역본 6) 번역본

40 영문 위해분석용어 의약품등시험방법 해설집 밸리데이션에대한 가이드라인해설서 2) 과학기술용어집 3) 한국표준과학연구원 기술표준원 KS CODEX 측정학용어사전 4) 용어 5) 규정번역본 6) 번역본

41 영문 위해분석용어 의약품등시험방법 해설집 밸리데이션에대한 가이드라인해설서 2) 과학기술용어집 3) 한국표준과학연구원 기술표준원 KS CODEX 측정학용어사전 4) 용어 5) 규정번역본 6) 번역본

42 영문 위해분석용어 의약품등시험방법 해설집 밸리데이션에대한 가이드라인해설서 2) 과학기술용어집 3) 한국표준과학연구원 기술표준원 KS CODEX 측정학용어사전 4) 용어 5) 규정번역본 6) 번역본

43 영문 위해분석용어 의약품등시험방법 해설집 밸리데이션에대한 가이드라인해설서 2) 과학기술용어집 3) 한국표준과학연구원 기술표준원 KS CODEX 측정학용어사전 4) 용어 5) 규정번역본 6) 번역본 1) 식품의약품안전청, ) 식품의약품안전청, ) 한국과학기술한림원, ) 한국표준과학연구원 ( 5) 기술표준원 ( 6) 보건복지가족부 식품의약품안전청, 2008

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45 CAC/GL Page 1 of 18 GUIDELINES ON ANALYTICAL TERMINOLOGY (CAC/GL ) INTRODUCTION The Codex Committee on Methods of Analysis and Sampling has agreed on Analytical Terminology for Codex Alimentarius and government use. A number of these terms were previously included in the Codex Procedural Manual. In most cases terms used in the Procedural Manual were adopted over time with an underlying hierarchy and can be traced verbatim to specific editions of ISO 3534, the GUM, the VIM, the IUPAC Orange Book or other international standards already adopted by Codex. Definitions of terms that have changed with newer editions of the international standards from which they were originally adopted have been updated preserving the original hierarchy found in the Procedural Manual. In cases where terms have been added in addition to those originally found in the procedural manual an effort has been made to preserve the conceptual continuity and relationship of the newer terms with extant ones. These terms, together with the terms which are included in specific International Protocols/Guidelines already adopted by Codex by reference are given below. ANALYTICAL TERMS The following analytical terms are defined below: Accuracy Analyte Applicability Bias Calibration Certified reference material Conventional quantity value Critical value Defining (Empirical) method of analysis Error Expanded measurement uncertainty Fitness for purpose HorRat Inter-laboratory study Laboratory performance (Proficiency) study Limit of detection Limit of quantification Linearity Material certification study Measurand Measurement method Measurement procedure Measurement uncertainty

46 CAC/GL Page 2 of 18 Method-performance study Metrological Traceability Outlier Precision Quality assurance Rational method of analysis Recovery/recovery factors Reference material Reference value Repeatability (Reproducibility) Repeatability conditions Repeatability (Reproducibility) limit Repeatability (Reproducibility) standard deviation Repeatability (Reproducibility relative standard deviation Reproducibility conditions Result Robustness (ruggedness) Selectivity Sensitivity Surrogate Systematic error Trueness True value Validated range Validated Test Method Validation Verification

47 CAC/GL Page 3 of 18 DEFINITIONS OF ANALYTICAL TERMS Accuracy: The closeness of agreement between a test result or measurement result and a reference value. Notes: The term accuracy, when applied to a set of test results or measurement results, involves a combination of random components and a common systematic error or bias component. When applied to a test method, the term accuracy refers to a combination of trueness and precision. ISO Standard : Vocabulary and Symbols Part 2: Applied Statistics, ISO, Geneva, 2006 Analyte: The chemical substance sought or determined in a sample. Note: This definition does not apply to molecular biological analytical methods. Codex Guidelines on Good Laboratory Practice in Residue Analysis (CAC/GL ) Applicability: the analytes, matrices, and concentrations for which a method of analysis may be used satisfactorily. Note: In addition to a statement of the range of capability of satisfactory performance for each factor, the statement of applicability (scope) may also include warnings as to known interference by other analytes, or inapplicability to certain matrices and situations. Codex Alimentarius Commission, Procedural Manual, 17 th Edition, 2007 Bias: The difference between the expectation of the test result or measurement result and the true value. In practice conventional quantity value (VIM, 2007) can be substituted for true value. Notes: Bias is the total systematic error as contrasted to random error. There may be one or more systematic error components contributing to bias. A larger systematic difference from the accepted reference value is reflected by a larger bias value. The bias of a measuring instrument is normally estimated by averaging the error of indication over the appropriate number of repeated measurements. The error of indication is the: indication of a measuring instrument minus a true value of the corresponding input quantity. Expectation is the expected value of a random variable, e.g. assigned value or long term average {ISO } ISO Standard : Vocabulary and Symbols Part 2: Applied Statistics, ISO, Geneva, 2006 Calibration: Operation that, under specified conditions, in a first step, establishes a relation between the values with measurement uncertainties provided by measurement standards and corresponding indications with associated measurement uncertainties and in a second step uses this information to establish a relation for obtaining a measurement result from an indication. Notes: A calibration may be expressed by a statement, calibration function, calibration diagram, calibration curve, or calibration table. In some cases it may consist of an additive or multiplicative correction of the indication with associated measurement uncertainty. Calibration should not be confused with adjustment of a measuring system often mistakenly called self calibration, or with verification of calibration.

48 CAC/GL Page 4 of 18 Often the first step alone in the above definition is perceived as being calibration. VIM, International Vocabulary of Metrology Basic and general concepts and associated terms, 3 rd edition, JCGM 200: 2008 Certified reference material (CRM): Reference material accompanied by documentation issued by an authoritative body and providing one or more specified property values with associated uncertainties and traceability, using valid procedures Notes: Documentation is given in the form of a certificate (see ISO guide 30:1992). Procedures for the production and certification of certified reference materials are given, e.g. in ISO Guide 34 and ISO Guide 35. In this definition, uncertainty covers both measurement uncertainty and uncertainty associated with the value of the nominal property, such as for identity and sequence. Traceability covers both metrological traceability of a value and traceability of a nominal property value. Specified values of certified reference materials require metrological traceability with associated measurement uncertainty {Accred. Qual. Assur., 2006} ISO/REMCO has an analogous definition {Accred. Qual. Assur., 2006} but uses the modifiers metrological and metrologically to refer to both quantity and nominal properties. VIM, International Vocabulary of Metrology Basic and general concepts and associated terms, 3 rd edition, JCGM 200: 2008 New definitions on reference materials, Accreditation and Quality Assurance, 10: , 2006 Conventional quantity value: quantity value attributed by agreement to a quantity for a given purpose. Notes: The term conventional true quantity value is sometimes used for this concept, but its use is discouraged. Sometimes a conventional quantity value is an estimate of a true quantity value. A conventional quantity value is generally accepted as being associated with a suitably small measurement uncertainty, which might be zero. VIM, International Vocabulary of Metrology Basic and general concepts and associated terms, 3 rd edition, JCGM 200: 2008 Critical value (L C ): The value of the net concentration or amount the exceeding of which leads, for a given error probability, to the decision that the concentration or amount of the analyte in the analyzed material is larger than that in the blank material. It is defined as: Pr ( >L C L=0) Where is the estimated value, L is the expectation or true value and L C is the critical value. Notes: The definition of critical value is important for defining the Limit of Detection (LOD). The critical value L c is estimated by L C = t 1- s o, Where t 1- is Student's-t, based on degrees of freedom for a one-sided confidence interval of 1-and s o is the sample standard deviation. If L is normally distributed with known variance, i.e. with the default of 0.05, L C = 1.645s o.

49 CAC/GL Page 5 of 18 A result falling below the L C triggering the decision not detected should not be construed as demonstrating analyte absence. Reporting such a result as zero or as < LOD is not recommended. The estimated value and its uncertainty should always be reported. References: ISO Standard 11843: Capability of Detection-1, ISO, Geneva, 1997 Nomenclature in evaluation of analytical methods, IUPAC, 1995 Defining (empirical/conventional) method of analysis: A method in which the quantity measured is defined by the result found on following the stated procedure. Notes: Empirical methods are used for purposes that cannot be covered by rational methods. Bias in empirical methods is conventionally zero. Harmonised guidelines for single-laboratory validation of methods of analysis, 2002 Error: Measured quantity value minus a reference quantity value. Note: The concept of measurement error can be used both: when there is a single reference value to refer to, which occurs if a calibration is made by means of a measurement standard with a measured value having a negligible measurement uncertainty or if a conventional value is given, in which case the measurement error is not known and if a measurand is supposed to be represented by a unique true value or a set of true values of negligible range, in which case the measurement error is not known. VIM, International Vocabulary of Metrology Basic and general concepts and associated terms, 3 rd edition, JCGM 200: 2008 Expanded measurement uncertainty: product of a combined standard measurement uncertainty and a factor larger than the number one Notes: The factor depends upon the type of probability distribution of the output quantity in a measurement model and on the selected coverage probability. The term factor in this definition refers to a coverage factor. Expanded measurement uncertainty is also termed expanded uncertainty. VIM, International Vocabulary of Metrology Basic and general concepts and associated terms, 3 rd edition, JCGM 200: 2008 Fitness for purpose: Degree to which data produced by a measurement process enables a user to make technically and administratively correct decisions for a stated purpose. Eurachem Guide: The fitness for purpose of analytical methods: A laboratory guide to method validation and related topics, 1998 HorRat: The ratio of the reproducibility relative standard deviation to that calculated from the Horwitz equation, Predicted relative standard deviation (PRSD) R =2C : HorRat(R) = RSD R /PRSD R, HorRat(r) = RSD r /PRSD R

50 CAC/GL Page 6 of 18 Where C is concentration expressed as a mass fraction (both numerator and denominator expressed in the same units). Notes: The HorRat is indicative of method performance for a large majority of methods in chemistry. Normal values lie between 0.5 and 2. (To check proper calculation of PRSD R, a C of 10-6 should give a PRSD R of 16 %.) If applied to within-laboratory studies, the normal range of HorRat(r) is For concentrations less than 0.12 mg/kg the predicted relative standard deviation developed by Thompson (The Analyst, 2000), 22% should be used. References: A simple method for evaluating data from an inter-laboratory study, J AOAC, 81(6): , 1998 Recent trends in inter-laboratory precision at ppb and sub-ppb concentrations in relation to fitness for purpose criteria in proficiency testing, The Analyst, 125: , 2000 Inter-laboratory study: A study in which several laboratories measure a quantity in one or more identical portions of homogeneous, stable materials under documented conditions, the results of which are compiled into a single document. Notes: The larger the number of participating laboratories, the greater the confidence that can be placed in the resulting estimates of the statistical parameters. The IUPAC-1987 protocol (Pure & Appl. Chem., 66, (1994)) requires a minimum of eight laboratories for method-performance studies. th Codex Alimentarius Commission, Procedural Manual, 17 Edition, 2007 Laboratory-performance (proficiency) study: An inter-laboratory study that consists of one or more measurements by a group of laboratories on one or more homogeneous, stable, test samples by the method selected or used by each laboratory. The reported results are compared with those from other laboratories or with the known or assigned reference value, usually with the objective of improving laboratory performance. Notes: Laboratory-performance studies can be used to support laboratory accreditation of laboratories or to audit performance. If a study is conducted by an organization with some type of management control over the participating laboratories: organizational, accreditation, regulatory or contractual, the method may be specified or the selection may be limited to a list of approved or equivalent methods. In such situations, a single test sample is insufficient to judge performance. A laboratory-performance study may be used to select a method of analysis that will be used in a methodperformance study. If all laboratories, or a sufficiently large subgroup, of laboratories, use the same method, the study may also be interpreted as a method-performance study, provided that the test samples cover the range of concentration of the analyte. Laboratories of a single organization with independent facilities, instruments, and calibration materials, are treated as different laboratories. Codex Alimentarius Commission, Procedural Manual, 17 Edition, 2007 th

51 CAC/GL Page 7 of 18 Limit of Detection (LOD): The true net concentration or amount of the analyte in the material to be analyzed which will lead, with probability (1- ), to the conclusion that the concentration or amount of the analyte in the analyzed material is larger than that in the blank material. It is defined as: Pr ( L C L=LOD) = Where is the estimated value, L is the expectation or true value and L C is the critical value. Notes: The limit of detection LOD is estimated by, LOD 2t 1- o [where =, Where t 1- is Student's-t, based on degrees of freedom for a one-sided confidence interval of 1-and o is the standard deviation of the true value (expectation). LOD = 3.29 o, when the uncertainty in the mean (expected) value of the blank is negligible, = = 0.05 and L is normally distributed with known constant variance. However, LOD is not defined simply as a fixed coefficient (e.g. 3, 6, etc.) times the standard deviation of a pure solution background. To do so can be extremely misleading. The correct estimation of LOD must take into account degrees of freedom, and, and the distribution of L as influenced by factors such as analyte concentration, matrix effects and interference. This definition provides a basis for taking into account exceptions to simple case that is described, i.e. involving non-normal distributions and heteroscedasticity (e.g. counting (Poisson) processes as those used for real time PCR). It is essential to specify the measurement process under consideration, since distributions, s and blanks can be dramatically different for different measurement processes. At the limit of detection, a positive identification can be achieved with reasonable and/or previously determined confidence in a defined matrix using a specific analytical method. References: ISO Standard 11843: Capability of Detection-1, ISO, Geneva, 1997 Nomenclature in evaluation of analytical methods, IUPAC, 1995 Guidance document on pesticide residue analytical methods, Organization for Economic Cooperation and Development, 2007 Limit of Quantification (LOQ): A method performance characteristic generally expressed in terms of the signal or measurement (true) value that will produce estimates having a specified relative standard deviation (RSD), commonly 10% (or 6%). LOQ is estimated by: LOQ = k Q Q, k Q = 1/RSD Q Where LOQ is the limit of quantification, Q is the standard deviation at that point and k Q is the multiplier whose reciprocal equals the selected RSD. (The approximate RSD of an estimated, based on -degrees of freedom is 1/ 2 Notes: If is known and constant, then Q = o, since the standard deviation of the estimated quantity is independent of concentration. Substituting 10% in for k Q gives: LOQ = (10 * Q ) = 10 o In this case, the LOQ is just 3.04 times the limit of detection, given normality and = = 0.05 At the LOQ, a positive identification can be achieved with reasonable and/or previously determined confidence in a defined matrix using a specific analytical method. This definition provides a basis for taking into account exceptions to the simple case that is described, i.e. involving non-normal distributions and heteroscedasticity (e.g. counting (Poisson) processes as those used for real time PCR).

52 CAC/GL Page 8 of 18 References: Nomenclature in evaluation of analytical methods, IUPAC, 1995 Guidance document on pesticide residue analytical methods, Organization for Economic Co-operation and Development, 2007 Linearity: The ability of a method of analysis, within a certain range, to provide an instrumental response or results proportional to the quantity of analyte to be determined in the laboratory sample. This proportionality is expressed by an a priori defined mathematical expression. The linearity limits are the experimental limits of concentrations between which a linear calibration model can be applied with an acceptable uncertainty. Codex Alimentarius Commission, Procedural Manual, 17 th Edition, 2007 Material-Certification Study: An inter-laboratory study that assigns a reference value ( true value ) to a quantity (concentration or property) in the test material, usually with a stated uncertainty. Note: A material-certification study often utilizes selected reference laboratories to analyse a candidate reference material by a method(s) judged most likely to provide the least-biased estimates of concentration (or of a characteristic property) and the smallest associated uncertainty. Codex Alimentarius Commission, Procedural Manual, 17 th Edition, 2007 Measurand: Quantity intended to be measured. Notes: The specification of a measurand requires knowledge of the kind of quantity, description of the state of the substance carrying the quantity, including any relevant component and the chemical entities involved. In chemistry, analyte or the name of a substance or compound are terms sometime used for measurand. This usage is erroneous because these terms do not refer to quantities. VIM, International Vocabulary of Metrology Basic and general concepts and associated terms, 3 rd edition, JCGM 200: 2008 Measurement method: Generic description of a logical organization of operations used in a measurement. Note: Measurement methods may be qualified in various ways such as: substitution measurement method, differential measurement method, and null measurement method; or direct measurement method, and indirect measurement method. VIM, International Vocabulary of Metrology Basic and general concepts and associated terms, 3 rd edition, JCGM 200: 2008 Measurement procedure: Detailed description of a measurement according to one or more measurement principles and to a given measurement method, based on a measurement model and including any calculation to obtain a result. Notes: A measurement procedure is usually documented in sufficient detail to enable an operator to perform a measurement. A measurement procedure can include a statement concerning a target measurement uncertainty. A measurement procedure is sometimes called a standard operating procedure (SOP).

53 CAC/GL Page 9 of 18 VIM, International Vocabulary of Metrology Basic and general concepts and associated terms, 3 rd edition, JCGM 200: 2008 Measurement uncertainty: Non-negative parameter characterizing the dispersion of the values being attributed to a measurand, based on the information used. Notes: Measurement uncertainty includes components arising from systematic effects, such as components associated with corrections and the assigned values of measurement standards, as well as the definitional uncertainty. Sometimes estimated systematic effects are not corrected for but, instead associated measurement uncertainty components are incorporated. The parameter may be, for example, a standard deviation called standard measurement uncertainty (or a given multiple of it), or the half-width of interval having a stated coverage probability. Measurement uncertainty comprises, in general many components. Some of these components may be evaluated by Type A evaluation of measurement uncertainty from the statistical distribution of the values from a series of measurements and can be characterized by experimental standard deviations. The other components which may be evaluated by Type B evaluation of measurement uncertainty can also be characterized by standard deviations, evaluated from assumed probability distributions based on experience or other information. In general, for a given set of information, it is understood that the measurement uncertainty is associated with a stated quality value attributed to the measurand. A modification of this value results in a modification of the associated uncertainty. VIM, International Vocabulary of Metrology Basic and general concepts and associated terms, 3 rd edition, JCGM 200: 2008 Method-Performance Study: An inter-laboratory study in which all laboratories follow the same written protocol and use the same test method to measure a quantity in sets of identical test samples. The reported results are used to estimate the performance characteristics of the method. Usually these characteristics are within-laboratory and among-laboratories precision, and when necessary and possible, other pertinent characteristics such as systematic error, recovery, internal quality control parameters, sensitivity, limit of quantification, and applicability. Notes: The materials used in such a study of analytical quantities are usually representative of materials to be analyzed in actual practice with respect to matrices, amount of test component (concentration), and interfering components and effects. Usually the analyst is not aware of the actual composition of the test samples but is aware of the matrix. The number of laboratories, number of test samples, number of determinations, and other details of the study are specified in the study protocol. Part of the study protocol is the procedure which provides the written directions for performing the analysis. The main distinguishing feature of this type of study is the necessity to follow the same written protocol and test method exactly. Several methods may be compared using the same test materials. If all laboratories use the same set of directions for each method and if the statistical analysis is conducted separately for each method, the study is a set of method-performance studies. Such a study may also be designated as a method-comparison study. Codex Alimentarius Commission, Procedural Manual, 17 th Edition, 2007 Metrological Traceability: Property of a measurement result whereby the result can be related to a reference through a documented unbroken chain of calibrations, each contributing to the stated measurement uncertainty.

54 CAC/GL Page 10 of 18 Notes: A reference can be a definition of a measurement unit through its practical realization, or a measurement procedure including the measurement unit for a non-ordinal quantity, or a measurement standard. Metrological traceability requires an established calibration hierarchy. Specification of the reference must include the time at which this reference was used in establishing the calibration hierarchy, along with any other relevant metrological information about the reference, such as when the first calibration in the calibration hierarchy was performed. For measurements with more than one input quantity each of the input values should itself be traceable and the calibration hierarchy involved may form a branched structure or network. The effort involved in establishing the metrological traceability for each input value should be commensurate with its relative contribution to the measurement result. Metrological traceability of a measurement result does not ensure that the measurement uncertainty is adequate for a given purpose or that there is an absence of mistakes. A comparison between two measurement standards may be viewed as a calibration if the comparison is used to check and if necessary correct the value and measurement uncertainty of the measurement standards. The ILAC considers the elements for confirming metrological to be an unbroken metrological traceability chain to an international measurement standard or a national measurement standard, a documented procedure, accredited technical competence, metrological to the SI and calibration intervals (see ILAC P- 10:2002) The abbreviated term traceability is sometimes used to mean metrological traceability as well as other concepts, such as sample traceability or document traceability or instrument traceability or material traceability, where history (trace) is meant. Therefore the full term of metrological traceability is preferred if there is any risk of confusion. VIM, International Vocabulary of Metrology Basic and general concepts and associated terms, 3 rd edition, JCGM 200: 2008 Harmonized guidelines for internal quality control in analytical chemistry laboratories, 1995 ILAC P-10, 2002 Outlier: A member of a set of values which is inconsistent with other members of that set Note: The following practice is recommended for dealing with outliers. a) Tests such as Cochran s or Grubb s tests are applied to identify stragglers or outliers: - if the test statistic is less than or equal to its 5 % critical value, the item tested is accepted as correct; - if the test statistic is greater than its 5 % critical value and less than or equal to its 1 % critical value, the item tested is called a straggler and is indicated by a single asterisk; - if the test statistic is greater than its 1 % critical value, the item is called a statistical outlier and is indicated by a double asterisk. b) It is next investigated whether the stragglers and/or statistical outliers can be explained by some technical error, for example: - a slip in performing the measurement, - an error in computation, - a simple clerical error in transcribing a test result, - analysis of the wrong sample. Where the error was one of the computation or transcription type, the suspect result should be replaced by the correct value; where the error was from analyzing a wrong sample, the result should be placed in its correct cell. After such correction has been made, the examination for stragglers or outliers should be repeated. If the explanation of the technical error is such that it proves impossible to replace the suspect

55 CAC/GL Page 11 of 18 test result, then it should be discarded as a genuine outlier that does not belong to the experiment proper. c) When any stragglers and/or statistical outliers remain that have not been explained or rejected as belonging to an outlying laboratory, the stragglers are retained as correct items and the statistical outliers are discarded unless the statistician for good reason decides to retain them. References: ISO Standard : Accuracy (trueness and precision) of measurement methods and results Part 1: General principles and definitions, ISO, Geneva, 1994 ISO Standard : Accuracy (trueness and precision) of measurement methods and results Part 2: Basic method for the determination of repeatability and reproducibility of a standard measurement method, ISO, Geneva, 1994 Precision: The closeness of agreement between independent test/measurement results obtained under stipulated conditions. Notes: Precision depends only on the distribution of random errors and does not relate to the true value or to the specified value. The measure of precision is usually expressed in terms of imprecision and computed as a standard deviation of the test results. Less precision is reflected by a larger standard deviation. Quantitative measures of precision depend critically on the stipulated conditions. Repeatability and reproducibility conditions are particular sets of extreme conditions. Intermediate conditions between these two extreme conditions are also conceivable, when one or more factors within a laboratory (intra-laboratory e.g. the operator, the equipment used, the calibration of the equipment used, the environment, the batch of reagent and the elapsed time between measurements) are allowed to vary and are useful in specified circumstances. Precision is normally expressed in terms of standard deviation. ISO Standard : Vocabulary and Symbols Part 2: Applied Statistics, ISO, Geneva, 2006 ISO Standard : Accuracy (trueness and precision) of measurement methods and results Part 3: Intermediate measures of the precision of a standard measurement method, ISO, Geneva, 1994 Quality assurance: All those planned and systematic actions necessary to provide adequate confidence that analytical results will satisfy given requirements for quality. Harmonized guidelines for internal quality control in analytical chemistry laboratories, 1995 Rational method of analysis: A method that determines an identifiable chemical(s) or analytes(s) for which there may be several equivalent methods of analysis available. Harmonized guidelines for the use of recovery information in analytical measurement, 1998 ISO/IEC Guide 17025:2005: General requirements for the competence of calibration and testing laboratories, ISO, Geneva, 2005 Recovery/recovery factors: Proportion of the amount of analyte, present in, added to or present in and added to the analytical portion of the test material, which is presented for measurement. Notes: Recovery is assessed by the ratio R = C obs / C ref of the observed concentration or amount C obs obtained by the application of an analytical procedure to a material containing analyte at a reference level C ref.

56 CAC/GL Page 12 of 18 C ref will be: (a) a reference material certified value, (b) measured by an alternative definitive method, (c) defined by a spike addition or (d) marginal recovery. Recovery is primarily intended for use in methods that rely on transferring the analyte from a complex matrix into a simpler solution, during which loss of analyte can be anticipated. Harmonized guidelines for the use of recovery information in analytical measurement, 1998 Use of the terms recovery and apparent recovery in analytical procedures, 2002 Reference material: Material, sufficiently homogeneous and stable with respect to one or more specified properties, which has been established to be fit for its intended use in a measurement process or in examination of nominal properties. Notes: Examination of a nominal property provides a nominal property value and associated uncertainty. This uncertainty is not a measurement uncertainty. Reference materials with or without assigned values can be used for measurement precision control whereas only reference materials with assigned values can be used for calibration and measurement trueness control. Some reference materials have assigned values that are metrologically traceable to a measurement unit outside a system of units. In a given measurement, a given reference material can only be used for either calibration or quality assurance. The specification of a reference material should include its material traceability, indicating its origin and processing. {Accred. Qual. Assur., 2006} ISO/REMCO has an analogous definition that uses the term measurement process to mean examination which covers both measurement of a quantity and examination of a nominal property. References: VIM, International Vocabulary of Metrology Basic and general concepts and associated terms, 3 rd edition, JCGM 200: 2008 New definitions on reference materials, Accred. Qual. Assur., 10: , 2006 Reference value: Quantity value used as a basis of comparison with values of quantity of the same kind. Notes: A reference quantity value can be a true quantity value of a measurand, in which case it is unknown, or a conventional quantity value in which case it is known. A reference quantity value with an associated measurement uncertainty is usually provided with reference to a) a material, e.g. a certified reference material b) a reference measurement procedure c) a comparison of measurement standards. VIM, International Vocabulary of Metrology Basic and general concepts and associated terms, 3 rd edition, JCGM 200: 2008 Repeatability (Reproducibility): Precision under repeatability (reproducibility) conditions. ISO Statistics, vocabulary and symbols-part 1: Probability and general statistical terms, ISO, 1993 ISO Standard 78-2: Chemistry Layouts for Standards Part 2: Methods of Chemical Analysis, 1999) Codex Alimentarius Commission, Procedural Manual, 17 th Edition, 2007

57 CAC/GL Page 13 of 18 AOAC International methods committee guidelines for validation of qualitative and quantitative food microbiological official methods of analysis, Repeatability conditions: Observation conditions where independent test/measurement results are obtained with the same method on identical test/measurement items in the same test or measuring facility by the same operator using the same equipment within short intervals of time. Note: Repeatability conditions include: the same measurement procedure or test procedure; the same operator; the same measuring or test equipment used under the same conditions; the same location and repetition over a short period of time. ISO Standard : Vocabulary and Symbols Part 2: Applied Statistics, ISO, Geneva, 2006 Repeatability (Reproducibility) limit: The value less than or equal to which the absolute difference between final values, each of them representing a series of test results or measurement results obtained under repeatability (reproducibility) conditions may be expected to be with a probability of 95%. Notes: The symbol used is r [R]. {ISO } When examining two single test results obtained under repeatability (reproducibility) conditions, the comparison should be made with the repeatability (reproducibility) limit, r [R] = 2.8 r[r]. {ISO , 4.1.4} When groups of measurements are used as the basis for the calculation of the repeatability (reproducibility) limits (now called the critical difference), more complicated formulae are required that are given in ISO : 1994, and ISO Standard : Vocabulary and Symbols Part 2: Applied Statistics, ISO, Geneva, 2006 ISO Accuracy (trueness and precision) of a measurement methods and results Part 6: Use in practice of accuracy value, ISO, 1994 Codex Alimentarius Commission, Procedural Manual, 17 th Edition, 2007 Repeatability (reproducibility) standard deviation: Standard deviation of test results or measurement results obtained under repeatability (reproducibility) conditions. Notes: It is a measure of the dispersion of the distribution of the test or measurement results under repeatability (reproducibility) conditions. ISO Standard : Vocabulary and Symbols Part 2: Applied Statistics, ISO, Geneva, 2006 Repeatability (reproducibility) relative standard deviation (coefficient of variation): Repeatability (reproducibility) standard deviation divided by the mean. RSD r[r] is computed by dividing the repeatability (reproducibility) standard deviation by the mean. Notes: Relative standard deviation (RSD) is a useful measure of precision in quantitative studies. This is done so that one can compare variability of sets with different means. RSD values are independent of the amount of analyte over a reasonable range and facilitate comparison of variabilities at different concentrations. The result of a collaborative test may be summarized by giving the RSD for repeatability (RSDr) and RSD for reproducibility (RSD R ). The RSD is also known as coefficient variation.

58 CAC/GL Page 14 of 18 ISO Standard : Vocabulary and Symbols Part 1: General statistical terms used in probability, ISO, Geneva, 2006 AOAC International methods committee guidelines for validation of qualitative and quantitative food microbiological official methods of analysis, Reproducibility conditions: Observation conditions where independent test/measurement results are obtained with the same method on identical test/measurement items in different test or measurement facilities with different operators using different equipment. ISO Standard : Vocabulary and Symbols Part 2: Applied Statistics, ISO, Geneva, 2006 Result: Set of values being attributed to a measurand together with any other available relevant information Notes: A result of measurement generally contains relevant information about the set of values, such that some may be more representative of the measurand than others. This may be expressed in the form of a probability density function. A result of measurement is generally expressed as a single measured value and a measurement uncertainty. If the measurement uncertainty is considered to be negligible for some purpose, the measurement result may be expressed as a single measured value. In many fields, this is the common way of expressing a measurement result. In the traditional literature and in the previous edition of the VIM, result was defined as a value attributed to a measurand and explained to mean an indication or an uncorrected result or a corrected result according to the context. VIM, International Vocabulary of Metrology Basic and general concepts and associated terms, 3 rd edition, JCGM 200: 2008 Robustness (ruggedness): A measure of the capacity of an analytical procedure to remain unaffected by small but deliberate variations in method parameters and provides an indication of its reliability during normal usage ICH Topic Q2 Validation of Analytical Methods, the European Agency for the Evaluation of Medicinal Products: ICH Topic Q 2 A - Definitions and Terminology (CPMP/ICH/381/95), 1995 Harmonized guidelines for single laboratory validation of methods of analysis, Pure and Appl. Chem., 2002 Selectivity: Selectivity is the extent to which a method can determine particular analyte(s) in a mixture(s) or matrice(s) without interferences from other components of similar behaviour. Note: Selectivity is the recommended term in analytical chemistry to express the extent to which a particular method can determine analyte(s) in the presence other components. Selectivity can be graded. The use of the term specificity for the same concept is to be discouraged as this often leads to confusion. Selectivity in analytical chemistry, IUPAC, Pure Appl Chem, 2001 Codex Alimentarius Commission, Alinorm 04/27/23, 2004 Codex Alimentarius Commission, Procedural Manual, 17 th Edition, 2007

59 CAC/GL Page 15 of 18 Sensitivity: Quotient of the change in the indication of a measuring system and the corresponding change in the value of the quantity being measured. Notes: The sensitivity can depend on the value of the quantity being measured The change considered in the value of the quantity being measured must be large compared with the resolution of the measurement system. VIM, International Vocabulary of Metrology Basic and general concepts and associated terms, 3 rd edition, JCGM 200: 2008 Surrogate: Pure compound or element added to the test material, the chemical and physical behaviour of which is taken to be representative of the native analyte. Harmonized guidelines for the use of recovery information in analytical measurement, 1998 Systematic error: Component of measurement error that in replicate measurements remains constant or varies in a predictable manner. Notes: A reference value for a systematic error is a true quantity value, or a measured value of a measurement standard of negligible measurement uncertainty, or a conventional value. Sytematic error and its causes can be known or unknown. A correction can be applied to compensate for a known systematic error. Systematic error equals measurement error minus random measurement error. VIM, International Vocabulary of Metrology Basic and general concepts and associated terms, 3 rd edition, JCGM 200: 2008 Trueness: The closeness of agreement between the average of an infinite number of replicate measured quantity values and a reference quantity value. Note 1: Measurement trueness is not a quantity and thus cannot be expressed numerically, but measures for closeness of agreement are given in ISO Note 2: Measurement trueness is inversely related to systematic measurement error, but is not related to random measurement error. Note 3: Measurement accuracy should not be used for 'measurement trueness' and vice versa. VIM, International Vocabulary of Metrology Basic and general concepts and associated terms, 3 rd edition, JCGM 200: 2008 True value: Quantity value consistent with the definition of a quantity. Notes: In the error approach to describing measurement, a true quantity value is considered unique and in practice unknowable. The uncertainty approach is to recognize that, owing to the inherently incomplete amount of detail in the definition of quantity, there is not a single true quantity value, but rather a set of quantity values consistent with the definition of a quantity. However, this set of values is, in principle and in practice unknowable. Other approaches dispense altogether with the concept of true quantity value and rely on the concept of metrological compatibility of measurement results for assessing their validity. When the definitional uncertainty associated with the measurand is considered to be negligible compared to the other components of the measurement uncertainty the measurand may be considered to have an essentially unique true value.

60 CAC/GL Page 16 of 18 VIM, International Vocabulary of Metrology Basic and general concepts and associated terms, 3 rd edition, JCGM 200: 2008 Validation: Verification, where the specified requirements are adequate for an intended use. VIM, International Vocabulary of Metrology Basic and general concepts and associated terms, 3 rd edition, JCGM 200: 2008 Validated Test Method: An accepted test method for which validation studies have been completed to determine the accuracy and reliability of this method for a specific purpose. ICCVAM Guidelines for the nomination and submission of new, revised and alternative test methods, 2003 Validated range: That part of the concentration range of an analytical method which has been subjected to validation. Harmonized guidelines for single-laboratory validation of methods of analysis, 2002 Verification: Provision of objective evidence that a given item fulfils specified requirements. Notes: When applicable method uncertainty should be taken into consideration. The item may be e.g. a process, measuring procedure, material, compound or measuring system. The specified requirement may be that a manufacturer s specifications are met. Verification in legal metrology, as defined in VIM and in conformity assessment in general pertains to the examination and marketing and/or issuing of a verification certificate for a measuring system. Verification should not be confused with calibration. Not every verification is a validation. In chemistry, verification of the identity of the entity involved or of the activity, requires a description of the structure and properties of that entity or activity. References: VIM, International Vocabulary of Metrology Basic and general concepts and associated terms, 3 rd edition, JCGM 200: 2008 REFERENCES 1. A simple method for evaluating data from an inter-laboratory study, J AOAC, 81(6): , AOAC International Methods committee guidelines for validation of qualitative and quantitative food microbiological methods of analysis, J AOAC, 85(5): , Codex Alimentarius Commission, Food and Agriculture Organization of the United Nations, World Health Organization, Alinorm 04/27/23, Report of the twenty-fifth session of the Codex Committee on Methods of Analysis and Sampling, Codex Alimentarius Commission, Procedural Manual, 17 th Edition, Food and Agriculture Organization of the United Nations, World Health Organization, Codex Alimentarius Commission, Food and Agriculture Organization of the United Nations, World Health Organization, Guidelines on Good Laboratory Practice in Residue Analysis (CAC/GL )

61 CAC/GL Page 17 of Commission Decision of 14 August 2002 implementing council directive 96/23/EC concerning the performance of analytical methods and the interpretation of results, The Commission of the European Communities, Compendium of Analytical Nomenclature, Definitive Rules, International Union of Pure and rd Applied Chemistry, 3 Edition, Eurachem Guide: The fitness for purpose of analytical methods: A laboratory guide to method validation and related topics, Guidance document on pesticide residue analytical methods, OECD health and safety publications, series on testing and assessment No. 72 and series on pesticides No. 39, Organization for Economic Co-operation and Development, Paris, GUM, Guide to the expression of uncertainty in measurement, ISO, Geneva, Harmonised guidelines for single-laboratory validation of methods of analysis, International Union of Pure and Applied Chemistry, Pure Appl. Chem., 74(5): , Harmonized guidelines for the use of recovery information in analytical measurement, IUPAC/ISO/AOAC International/Eurachem technical report, ICCVAM Guidelines for the nomination and submission of new, revised and alternative test methods, Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), National Institute of Environmental Health Sciences, US Department of Health and Human Services, ICH Topic Q2 Validation of Analytical Methods, The European Agency for the Evaluation of Medicinal Products: ICH Topic Q 2 A - Definitions and Terminology (CPMP/ICH/38 1/95), ILAC P-10, ILAC policy on traceability of measurement results, ISO/IEC Guide 17025:2005: General requirements for the competence of calibration and testing laboratories, ISO, Geneva, ISO Standard 11843: Capability of Detection-1, ISO, Geneva, ISO Standard : Vocabulary and Symbols Part 1: Applied Statistics, ISO, Geneva, ISO Standard : Vocabulary and Symbols Part 2: Applied Statistics, ISO, Geneva, ISO Standard : Accuracy (trueness and precision) of measurement methods and results, Part 1: General principles and definitions, ISO, Geneva, ISO Standard : Accuracy (trueness and precision) of measurement methods and results Part 3: Intermediate measures of the precision of a standard measurement method, ISO, Geneva, ISO Standard 78-2: Chemistry layouts for standards Part 2: Methods of chemical analysis, ISO, second edition, New definitions on reference materials, Accreditation and Quality Assurance, 10: , Nomenclature for the presentation of results of chemical analysis, International Union of Pure and Applied Chemistry, Pure and Applied Chemistry, 66(3): , Nomenclature in evaluation of analytical methods including detection and quantification capabilities, International Union of Pure and Applied Chemistry, Pure and Applied Chemistry, 67(10): , OIML V1:2000, International vocabulary of terms in legal metrology, Polymerase chain reaction technology as an analytical tool in agricultural biotechnology, J AOAC, 88(1): , Practical procedures to validate method performance and results for analysis of pesticides and veterinary drug residues and organic contaminants in food, A. Ambrus, International workshop on principles and practices of method validation, FAO/IAEA/AOAC/IUPAC, p.37, Budapest, Protocol for the design, conduct and interpretation of method-performance studies, International

62 CAC/GL Page 18 of 18 Union of Pure and Applied Chemistry, Pure Appl. Chem. 67(2): , Quality management and quality assurance-vocabulary ISO 8402, second edition, Recent trends in inter-laboratory precision at ppb and sub-ppb concentrations in relation to fitness for purpose criteria in proficiency testing, The Analyst, 125: , Selectivity in Analytical Chemistry, International Union of Pure and Applied Chemistry, Pure Appl. Chem., 73(8): , Terms and definitions used in connections with reference materials, ISO Guide 30: The harmonised guidelines for internal quality control in analytical chemistry laboratories, International Union of Pure and Applied Chemistry, Pure Appl. Chem., 67: , The international harmonised protocol for the proficiency testing of (chemical) analytical laboratories, International Union of Pure and Applied Chemistry, Pure Appl. Chem., 65, , Use of the terms recovery and apparent recovery in analytical procedures, International Union of Pure and Applied Chemistry, Pure Appl. Chem., 74(11): , VIM, International vocabulary of metrology - Basic and general concepts and associated terms, JCGM 200: 2008, also published as ISO/IEC Guide 99-12:2007.

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